Naked mole rats feel no pain due to acid

Acid inhibition of ion channels is more potent in naked mole rats than in …

African naked mole rats never cease to amaze. Not only are they exceedingly ugly, but they are the longest living rodents. Moreover, none have ever been observed to get cancer. And they are the only known vertebrates that are not bothered by acid. A report in this week’s Science explains the molecular basis underlying this acid insensitivity, and suggests that it might be an adaptation to their oxygen-poor living conditions..

Acid causes pain by activating nociceptors, proton-triggered ion channels that activate neurons. This recent study compared acid receptors from naked mole rats and mice, and found that they were not all that different. Similar numbers of each receptor were found in the respective animals, and acid evoked similar levels of current through them.

Voltage gated sodium channels, which function in the propagation of nerve signals, are known to be inhibited by protons. It turns out that voltage-gated currents in the naked mole rat are much more susceptible to acid inhibition than those in mice. At pH6.0, the naked mole rat neurons exhibited a 63 percent reduction in conductance, which was significantly greater than the 42 percent reduction observed in the mouse neurons.

Mild acidification shuts down both mouse and naked mole rat channels, preventing them from opening when confronted with a much lower pH. But this inactivation happens much faster in the naked mole rat.

How and why does acid inhibit naked mole rat nociceptors so potently? The threshold for triggering a nerve impulse by nociceptors is determined by a specific sodium gated channel. In humans, genetic mutations disabling the gene encoding this channel lead to complete insensitivity to pain, whereas activating mutations cause extreme pain disorders.

Within the pore of this channel, there is a string of positively charged amino acids that controls acid sensitivity. In naked mole rats, these are replaced by negatively charged amino acids. The amino acid changes in the naked mole rat cause an increased proton sensitivity in their sodium channel, providing an inhibition too strong for acid to overcome. Thus acid cannot evoke nociceptor firing like it can in other animals.

Naked mole rats live in large colonies in underground burrows, which incidentally is why they are naked—they don’t need any fur. But their subterranean environment is very high in CO2, which can lower the pH of tissues.

There is also a species of microbat that lives in small caves and is therefore also subjected to a high CO2 environment. Its sodium channel has a negatively charged motif in it like the naked mole rat's, instead of a positively charged one like ours. Convergent evolution thus may have selected for these genetic variants to reduce acid sensitivity in these very different species that share similar extreme living conditions.